Perioperative chemotherapy in the treatment of osteosarcoma: a 26-year single institution review.

BACKGROUND: Chemotherapy in the multimodality treatment of osteosarcoma has improved survival. Reported outcomes on adult patients are limited. Poor necrosis rates post neoadjuvant chemotherapy (NAC) is considered an adverse prognostic factor and attempts have been made to improve survival in this group. PATIENTS AND METHODS: Adult and young adult patients diagnosed with osteosarcoma between January 1986 and August 2012 were retrospectively reviewed. Patients identified were stratified according to stage (localised or metastatic) and age (≤40 and >40 years). Event free survival (EFS) and overall survival (OS) outcomes were determined. In patients with localised disease ≤40 years, survival was assessed according to necrosis rates post NAC (<90 and ≥90%). NAC consisted of two cycles of methotrexate alternating with doxorubicin/cisplatin (MAP) followed by definitive surgery. Those with ≥90% tumour necrosis continued on MAP. Patients with <90% necrosis received ifosfamide and etoposide (IE) post operatively. RESULTS: A total of 108 patients were reviewed and 97 were included. Median age was 23 years (range 16-75) and 70% of patients were male. Five year EFS and OS across all groups was 57% and 63% respectively. Of the patients with localised disease (N = 81), 5-year overall survival (OS), with a median follow up of 7 years (2-26) was 70% (p < 0.0001). Patients aged 16-40 (N = 68) with localised osteosarcoma had a significantly improved 5-year OS (74%) compared to those >40 years (N = 13) (42%) (p = 0.004). Of the 68 patients with localised osteosarcoma ≤40 years, 62 were evaluated according to necrosis rates post MAP. In 33 patients who achieved ≥90% necrosis and continued MAP, 5-year OS was 82%. In 29 patients who had <90% tumour necrosis and received adjuvant IE, 5-year OS was 68% (p = 0.15). Multivariate analysis confirmed age and stage as prognostic factors but not poor necrosis rates in our treated population. CONCLUSIONS: Long-term survival outcomes in a predominantly adult Irish population are similar to large reported trials. Age and stage at diagnosis are prognostic. Postoperative ifosfamide/etoposide alone in patients with poor necrosis rates is a feasible regimen, but its role in the adjuvant setting remains uncertain.

Cost induced by hip fractures.

Hip fracture is the most common fracture in the elderly population. Treating hip fractures is a major burden on the Irish Health system. There is no recent Republic of Ireland study detailing hospital costs for such injuries. A comprehensive analysis of 143 patients admitted with a hip fracture was performed to determine current medical expenditure incurred during acute hospitalization for hip fractures during 2005 in a major university hospital. Costs associated with surgery (implant & theatre costs), laboratory, radiology, physiotherapy and ward were calculated on individual basis. All the hip fractures were above 60 years of age (mean 82 years); average stay in the hospital was 11 days. The mean total hospital expenditure per patient was Euro 9236.01 of which ward costs contributed 55.33%, operative costs 39.82% and investigations 4.83%. The result clearly show that hip fractures have a major economic impact arising from the inpatient treatment, most of which relate to length of hospital stay.

Skeletal muscle metastasis from uterine leiomyosarcoma.

A case of a 68-year-old woman who presented with a rapidly enlarging painful right thigh mass is presented. She had a known diagnosis of uterine leiomyosarcoma following a hysterectomy for dysfunctional uterine bleeding. She subsequently developed a single hepatic metastatic deposit that responded well to radiofrequency ablation. Whole-body MRI and MRA revealed a vascular mass in the sartorius muscle and a smaller adjacent mass in the gracilis muscle, proven to represent metastatic leiomyosarcoma of uterine origin. To our knowledge, metastatic uterine leiomyosarcoma to the skeletal muscle has not been described previously in the English medical literature.

Pectoralis major tendon ruptures: when to operate.

The treatment of pectoralis major tendon ruptures has been the subject of much debate. The classical history of the injury is forced abduction and external rotation. The cases of two patients (an amateur rugby union player and a recreational snowboarder) are reported. The diagnosis was made by clinical examination in both patients, and both were operated on more than two weeks after injury. After surgery and a graduated rehabilitation programme, both men were able to return to their sporting activities. These two cases highlight the advantage of operative management in this uncommon condition.

Extraskeletal Ewing's sarcoma: a case report and review of the literature.

STUDY DESIGN: Case report. OBJECTIVES: To report on the diagnosis and current treatment of a rare tumor about the cervical spine. SUMMARY OF BACKGROUND DATA: Extraskeletal Ewing's sarcoma (EES) is rare and has not been previously described about the cervical spine. We present a case of a 24-year-old man with a large mass in the posterior triangle of the neck extending through the vertebral foramens of the cervical vertebrae. This was identified as an extraskeletal Ewing's sarcoma. Traditional treatment paradigms have been associated with a poor prognosis. Since the recommendations of the Intergroup Rhabdomyosarcoma Study II study of multimodal chemotherapy and radiotherapy, this tumor has a significantly better prognosis. METHOD: Surgical debulking of the tumor was necessary to relieve cord compression. Histologic analysis was used to confirm both magnetic resonance imaging and computed tomography diagnosis. A chemoradiation therapy program was commenced in accordance with Intergroup Rhabdomyosarcoma Study II recommendations. RESULTS: Computed tomography and magnetic resonance imaging demonstrated a large lobulated mass extending through the exit foramens of C2/C3 and C3/C4. The mass was entirely extraskeletal and extradural. Histologic examination of the excised mass showed microscopy consistent with extraskeletal Ewing's sarcoma. After surgical debulking and chemoradiation, the patient made a complete recovery. CONCLUSION: A review of the literature confirms that extraskeletal Ewing's sarcoma is a rare tumor and particularly so in the region of the cervical spine. Early diagnosis and surgical debulking combined with current multimodality chemoradiation programs can produce a favorable outcome.

Surgery for locally aggressive bone tumours.

Treatment of 16 patients with aggressive benign bone tumours and one patient with a low grade malignancy with a combined regimen of cryosurgery, phenolization and acrylic cementation is reported. Patients were aged between 9 and 51 years and were treated by this method between the years 1986 and 1993. Minimal follow up was 13 months. The commonest histological diagnosis was giant cell tumour (7), followed by aneurysmal bone cyst (6), chondromyxoidfibroma (3) and low grade chondrosarcoma (1). Patients were assessed for functional outcome and local recurrence. On average 86 per cent of premorbid function was restored at follow up and there was one local recurrence (6.29 per cent). We conclude that this is a satisfactory method of gaining local control of these tumours.

T-cell and macrophage subsets in the bronchial wall of clinically healthy subjects.

This study was conducted to obtain quantitative data on the numbers of T-cells and macrophage subsets in the normal bronchial wall of man, and, thus, produce a baseline against which the numbers of these cells present in inflamed bronchi may be judged. Bronchial biopsies were obtained from 27 clinically healthy subjects attending hospital for elective orthopaedic operations. Eight of the subjects were smokers (median 3.5 pack-years), and eight were atopic as defined by skin prick test. Three to eight weeks after biopsy, subjects attended the lung function laboratory for spirometric testing and determination of provocative concentration of histamine producing a 20% fall in forced expiratory volume in one second (PC20FEV1). The bronchial biopsies were frozen and cryostat sections prepared. These sections were investigated with immunohistological techniques to reveal the presence and distribution of T-cell and macrophage subsets. Twenty six out of 27 subjects had spirometric values within the normal range, but a wide spectrum of bronchial reactivity was observed (PC20FEV1 range 2-36 mg histamine). Using monoclonal antibodies in immunohistological techniques, only small numbers of T-cells were seen, the majority being CD8+ cells in the epithelium. In the underlying tissue, CD4+ cells predominated (CD4/CD8 ratio, epithelium 1:9; underlying tissue 4:1). In both cases, approx. 50% of T-cells expressed the CD45Ro isotype. Small numbers of macrophages were observed in all samples. The majority of these cells expressed a "suppressor cell" phenotype (RFD1+RFD7+), whilst only a small proportion (median 11% ) exhibited the phenotype of antigen presenting cells (RFD1+RFD7-).(ABSTRACT TRUNCATED AT 250 WORDS)

Distribution of immunocompetent cells in the bronchial wall of clinically healthy subjects showing bronchial hyperresponsiveness.

BACKGROUND: Nearly all asthmatic subjects show bronchial hyperresponsiveness, in that the provocative concentration of histamine reducing forced expiratory volume in one second (FEV1) by 20% (PC20FEV1) is < or = 8 mg/ml histamine, and have underlying chronic inflammation of the bronchial wall mediated by T cells. The possible cause and effect relationship between these phenomena remains an enigma. As a proportion of clinically healthy subjects show bronchial hyperresponsiveness, this study was undertaken to determine whether they also show evidence of bronchial inflammation. METHODS: Bronchial biopsy specimens were obtained from 27 clinically healthy subjects with no history of lung disease. Samples were taken perioperatively before elective knee arthroscopy for sports injuries. Specimens were frozen and cryostat sections analysed immunocytochemically with monoclonal antibodies to identify the presence of T lymphocytes, antigen presenting cells, and the expression of HLA-DR. Double immunofluorescence studies were performed with monoclonal antibodies RFD1 and RFD7 to show the relative proportions of RFD1+ RFD7- antigen presenting cells, RFD1- RFD7+ mature phagocytes, and RFD1+ RFD7+ suppressor macrophages. Histological stains were performed to show the presence of eosinophils and mast cells. Three to four weeks after bronchoscopy spirometry was performed on these subjects to record FEV1, forced vital capacity (FVC), FEV1/FVC, and forced expiratory flow between 25% and 75% of vital capacity (FEF25-75). Bronchial hyperreactivity was recorded by determining PC20FEV1 to histamine. RESULTS: Nine of the 27 subjects showed bronchial hyperresponsiveness as defined by a PC20FEV1 of < or = 8 mg/ml histamine. Segregated subjects with and without bronchial hyperresponsiveness showed no difference in spirometric results. Immunohistological analysis showed no evidence of inflammation in either group. Numbers of T cells, eosinophils, and mast cells were the same in both groups as was the expression of HLA-DR antigen. No neutrophils were observed in any tissues. Interestingly, reduced numbers of macrophages with the phenotype of antigen presenting cells (monoclonal antibodies RFD1+ RFD7-) were recorded in the subjects with bronchial hyperresponsiveness, who also had a significant increase in the proportion of RFD1+ RFD7+ suppressor macrophages. CONCLUSIONS: Up to 30% of selected clinically healthy subjects may have a PC20FEV1 of < or = 8 mg/ml histamine. This physiological trait can exist in the absence of bronchial inflammation. This suggests that bronchial hyperresponsiveness as currently defined is not dependent on immunopathological changes in the bronchial wall and does not necessarily promote even subclinical inflammation.

Effects of intraarticular morphine on analgesic requirements after anterior cruciate ligament repair.

BACKGROUND AND OBJECTIVES: Intraarticular morphine has been shown to provide postoperative pain relief after knee arthroscopy. The analgesia results from local action within the knee joint. This study was conducted to assess the efficacy of intraarticular morphine as a treatment for postoperative pain after anterior cruciate ligament repair. METHODS: A randomized double blind-study was conducted in patients undergoing elective anterior cruciate ligament repair. Patients in the study group (n = 10) received intraarticularly 5 mg of morphine in a 25 ml dilution. Those in the control group (n = 10) received 25 ml of saline by the same route. Intravenous morphine with patient-controlled analgesia was used in the postoperative period in both the groups. Visual analog scores were recorded at 1, 2, 4, 8, and 24 hours after the operation. The amount of morphine used over the 24-hour postoperative period was documented. RESULTS: The total consumption of morphine over the 24-hour period was significantly lower (p < 0.01) in the study group compared to the control group. The postoperative pain scores were lower in the study group throughout the study period, but this did not reach statistical significance. CONCLUSIONS: Intraarticular morphine reduces analgesic requirements after anterior cruciate ligament repair and is an effective method of providing postoperative analgesia.

Intra-articular morphine for pain relief after anterior cruciate ligament repair.

We have performed a randomized, double-blind controlled study in patients undergoing elective anterior cruciate ligament repair, to assess the effect of intra-articular morphine on postoperative pain. The morphine group (n = 11) received morphine 5 mg in saline 25 ml and the control group (n = 9), saline 25 ml intra-articularly. Patients in the morphine group had significantly smaller pain scores throughout the 24-h postoperative period compared with those in the control group (P < 0.05). There was less requirement for supplementary analgesics in the morphine group.

Tissue characterization and assessment of preoperative chemotherapeutic response in musculoskeletal tumors by in vivo 31P magnetic resonance spectroscopy.

This study investigates the potential of in vivo 31P magnetic resonance spectroscopy (MRS) to characterize musculoskeletal tumors and to determine preoperative levels of histological necrosis, which is an important clinical indicator of patient response. Pretherapy MRS was performed on 28 patients with large musculoskeletal tumors: 13 with osteosarcoma, 3 with chondrosarcoma, 5 with malignant fibrous histiocytoma, 1 with desmoid tumor, 1 with Ewing's, 2 with hemangioendothelioma, 1 with myxoid liposarcoma, 1 with synovial cell sarcoma, and 1 with rhabdomyosarcoma. Fifteen patients had follow-up MRS examinations after commencement of chemotherapy (mean of five/patient), eight of whom have now had surgery. Elevated levels of PMEs (P < 0.01), P(i) (P < 0.01), and PDEs (P < 0.02) as well as elevated tumor pH (P < 0.05) were observed in all patients. The synovial cell sarcoma was characterized by high levels of PMEs (> 20%) and low pH (pH 6.76). This contrasted with the spectra obtained from the malignant fibrous histiocytomas which had high levels of PDEs (17 +/- 5%). Reductions in PDE levels postchemotherapy were associated with a high degree of necrosis (> 90%) at surgery, while an increase in PDE levels was associated with a low level of histological necrosis. Likewise, reductions in the ratios PDE/NTP and PDE/PCr and an increase in P(i)/PDE were also associated with a high level of necrosis.

31P MRS as an early prognostic indicator of patient response to chemotherapy.

In this study 31P spectral changes were closely monitored following the initial administration of cytotoxic drugs and related to five parameters of patient response. Pre- and postchemotherapy 31P MRS examinations were performed on 16 patients with large, malignant tumors. These included four tumor types: (i) lymphoma (n = 7), (ii) breast carcinoma (n = 4), (iii) musculoskeletal tumors (n = 4), and (iv) adenocarcinoma (n = 1). A mean of 5 spectra/patient (range 2-10) was performed following the initial chemotherapy. The spectral trends exhibited by 14 of 16 patients reached "points of maximum change," after which they began to revert toward prechemotherapy values. In 2 of 16 patients that did not respond to the initial chemotherapy regimen, no spectral trends were observed. The degree of change of certain spectral parameters, namely, decreases in PME, PME/PDE, PME/PCr, PME/NTP, PDE/PCr, and tumor pH, as well as increases in the ratios Pi/PME and Pi/PDE, were associated with good patient response and separated responders from nonresponders. Pi/PME appears the most promising for discriminating partial from complete responders.

Imaging of intramedullary tumour spread in osteosarcoma. A comparison of techniques.

The level of bone resection for osteosarcoma depends on the pre-operative evaluation of the extent of intramedullary tumour. We compared the accuracy of magnetic resonance imaging (MRI), computerised tomography (CT), and isotope bone scanning with the actual extent of the tumour in the resected specimens from 34 patients with primary osteosarcoma of a long bone. The extent of medullary tumour was defined accurately in 23 of 24 MRI scans (96%) and 24 of 32 CT scans (75%). A flexion contracture of a joint close to the tumour was an important cause for inaccurate measurements from both MRI and CT scans. Isotope bone scanning was inaccurate: its role is now confined to detecting skeletal metastases and skip lesions.

Biopsy problems in patients with musculoskeletal tumours.

The problems of biopsy procedures and the effect that these had on subsequent surgery were studied in fifty one consecutive patients with musculoskeletal tumours. Difficulties included inadequate tissue for histology in 4 patients, wound infection in 5, haematoma formation in 2, inappropriate biopsy site in 7 and incorrect placement of drain exit site in 4. Open biopsy gave a more reliable diagnosis than needle biopsy, but was associated with a higher incidence of complications. Staging techniques such as magnetic resonance imaging, computed tomography and bone scans were less accurate when performed after the biopsy. Longitudinal incisions, centred over representative tumour tissue with the drain site placed in line with the incision, facilitate the adequate and uncomplicated removal of the entire biopsy scar and tract at the time of the definitive surgical procedure. It is concluded that biopsy for suspected musculoskeletal tumours should not be delegated to junior residents and should be performed in centres that have experience in the management of such tumours.

Osteosarcoma: use of MR imaging and MR spectroscopy in clinical decision making.

Magnetic resonance (MR) imaging was performed on 14 patients with histologically proved osteosarcoma (mean age, 14.4 years). There was excellent correlation of intramedullary tumor extent as determined with MR imaging and pathologic examination (r = 99%). This was facilitated by the presence of a chemical shift artifact at the tumor-marrow interface on the T1-weighted images. The correlation between CT and pathologic findings was not as good (r = 84%). In a single patient, however, a 10-cm length of sclerotic bone was incorrectly interpreted as being tumor. If this case is excluded, the correlation between CT and pathologic findings improves significantly (r = 96%). T2-weighted images were optimal in demonstrating soft-tissue bulk and breach of the epiphysis or cortex. Vascular involvement was also readily defined. The T2 value of the tumor soft-tissue component decreased in patients who were deemed to have responded well to therapy. Two patients with very high T2 values after chemotherapy developed wide-spread metastatic disease and died. Phosphorus-31 MR spectroscopy of five patients with osteosarcoma showed elevated levels of phosphomonoesters (PMEs), inorganic phosphate (Pi), and phosphodiesters (PDEs). PME and PDE peak areas decreased in three patients after chemotherapy, while Pi peak areas increased.

Dedifferentiated chondrosarcoma with muscle and cytokeratin differentiation in the anaplastic component.

Dedifferentiated chondrosarcoma is a biphasic tumour, comprising well-differentiated chondrosarcoma and an anaplastic non-cartilaginous sarcoma juxtaposed but distinct from each other. Two cases of dedifferentiated chondrosarcoma, one primary and one recurrent, demonstrated muscle differentiation when studied with monoclonal antibodies to muscle specific actin, desmin and myoglobin. One of the tumours was also positive for cytokeratin, identified by AE1/AE3 and CAM 5.2 antibodies. Our findings are consistent with the concept that these tumours are capable of diverse patterns of morphological and immunophenotypic differentiation.

Osteogenic sarcoma.

Guarded optimism could be clearly stated for the treatment of osteogenic sarcoma. Improved methods of diagnosis and staging have been made possible by the computed tomography (CT) scan and other new modalities. The advent of pre- and postoperative chemotherapy has significantly enhanced survival rates that are now approaching 85%. Improved concepts of en bloc resection and better reconstructive techniques suggest that limb salvage procedures are not only possible but can provide excellent functional results in the context of muscle loss. Continued work must be directed toward improving the reconstructive techniques to provide implants with permanence, particularly for young patients and to clearly define the indications for such procedures. Patients presenting with thoracic lesions, although difficult to treat, can expect a 30%--45% long-term survival following repetitive thoracotomies.

Treatment of rheumatoid synovitis of the knee with intraarticular injection of dysprosium 165-ferric hydroxide macroaggregates.

One hundred eight knees of 93 patients with seropositive rheumatoid arthritis and persistent synovitis of the knee were treated with an intraarticular injection of 270 mCi of dysprosium 165 bound to ferric hydroxide macroaggregate. Leakage of radioactivity from the injected joint was minimal. Mean leakage to the venous blood 3 hours after injection was 0.11% of the injected dose; this corresponds to a mean whole body dose of 0.2 rads. Mean leakage to the liver 24 hours after injection was 0.64% of the injected dose; this corresponds to a mean liver dose of 3.2 rads. In 7 additional patients examined, there was negligible or near negligible activity found in the draining inguinal lymph nodes. One-year followup was possible for 74 knees (63 patients). Sixty-one percent of the knees had good results, 23% had fair results, and 16% had poor results. There was a direct correlation between the radiographic stage and response to treatment. In knees with stage I radiographic changes, 72% showed good results; 93% showed improvement. In knees with stage II changes, 59% showed good results; 81% showed improvement. These preliminary results indicate that dysprosium 165-ferric hydroxide macroaggregate is an effective agent for radiation synovectomy. The low leakage rates observed offer a definite advantage over agents previously used.